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Try out PMC Labs and tell us what you think. Learn More. During ageing, the secretory patterns of the hormones produced by the hypothalamic—pituitary axis change, as does the sensitivity of the axis to negative feedback by end hormones. Additionally, glucose homoeostasis tends towards disequilibrium with increasing age. Along with these endocrine alterations, a loss of bone and muscle mass and strength occurs, coupled with an increase in fat mass. In addition, ageing-induced effects are difficult to disentangle from the influence of other factors that are common in older people, such as chronic diseases, inflammation, and low nutritional status, all of which can also affect endocrine systems.
Traditionally, the decrease in hormone activity during the ageing process has been considered to be detrimental because of the related decline in bodily functions. The concept of hormone replacement therapy was suggested as a therapeutic intervention to stop or reverse this decline.
However, clearly some of these changes are a beneficial adaptation to ageing, whereas hormonal intervention often causes important adverse effects. In this paper, we discuss the effects of age on the different hypothalamic—pituitary—hormonal organ axes, as well as age-related changes in calcium and bone metabolism and glucose homoeostasis. Throughout adult life, all physiological functions begin to gradually decline. Ageing is characterised by changes in virtually all biological systems. Major changes to the endocrine system, as described in this Series paper, result in healthy ageing individuals with well recognised phenotypes.
However, other factors, such as inflammation and calorie intake, also affect the ageing process, and are often associated with age-related chronic diseases. These factors make the role of changes in hormonal activity difficult to disentangle and clarify in clinical practice.
The triggers that determine the ageing process in the hypothalamus and pituitary have ly been reviewed. Several population studies, 3 — 6 but not all, 78 show that after the exclusion of people with thyroid disease and people with positive anti-thyroid antibodies, normal ageing is accompanied by an increase in the concentration of serum thyroid-stimulating hormone TSH. However, changes in TSH concentration seem to be dependent on the regional iodine status, and could reflect a survival bias. Each datapoint represents one of a cohort of men aged 73—94 years living in the Netherlands.
Reproduced from van den Beld and colleagues, 11 by permission of Oxford University Press. Whether the increased prevalence of subclinical hypothyroidism and hyperthyroidism at an older age 14 and the increase in TSH within the normal reference range during ageing is of clinical relevance remains a matter of debate.
Pooled data show that subclinical hyperthyroidism is associated with an increased risk of overall and cardiovascular-related mortality, especially in older people and patients with comorbidities. In contrast, older individuals with subclinical hypothyroidism or higher TSH concentrations within the normal range have a lower mortality than do euthyroid individuals or people with lower TSH concentrations.
Higher TSH concentrations within the reference range appear to even decrease the risk of stroke. These findings suggest that slightly lower hypothalamic-pituitary-thyroid axis activity is beneficial during the ageing process. This hypothesis is also supported by a series of studies that link low thyroid hormone concentrations to reduced frailty.
In conclusion, the ageing process modulates the concentration of thyroid hormones. These alterations are highly variable among individuals, but overall thyroid hormone axis activity seems to decline with age, and this decline in activity is reflected by an increase in TSH and a decrease in T 3 concentrations. However, these age-associated changes are not related to a detrimental ageing process, and might even be beneficial.
Therefore, age-specific hormone reference ranges are useful to avoid misclassifying and overtreating older people, although so far, these age-specific thyroid function reference ranges are still lacking. The hypothalamic—pituitary—somatotropic axis is a hypothalamic—pituitary axis that includes the secretion of growth hormone somatotropin from the somatotropes of the pituitary gland into the circulation, and the subsequent stimulation of insulin-like growth factor-1 IGF The somatopause is a gradual and progressive decrease in growth hormone secretion that occurs normally with increasing age during adult life, and is associated with an increase in adipose tissue.
This decline in growth hormone after puberty continues during adult life and ageing, and consequently plasma growth hormone concentrations, and therefore IGF-1 concentrations, in older individuals are lower than in young adults.
Age-related decline in growth hormone concentrations is well documented, consistent across different mammalian species, and primarily due to the reduced hypothalamic secretion of growth hormone-releasing hormone, causing the decline of growth hormone biosynthesis and release by the anterior pituitary. Moreover, although growth hormone therapy has been shown to exert positive effects on growth hormone-deficient patients, its safety, efficacy, and role in healthy older individuals is highly controversial.
Research focused on investigating brain structure and function in patients with Laron syndrome, the best characterised congenital IGF-1 deficiency, suggests that, compared with controls, older patients with Laron syndrome have brain structure and function that are consistent with those of younger adults. This observation raises the possibility that growth hormone receptor inhibition has the potential to protect against age-dependent cognitive decline.
In conclusion, ageing and the so-called somatopause are accompanied by a decrease in the concentrations of growth hormone and IGF-1, but no single intervention has been proven to be effective at halting or reversing somatopause. Appetite and food intake decrease with normal ageing, predisposing older individuals to become undernourished. Possible hormonal causes of the anorexia of ageing include increased activity of cholecystokinin, leptin, and various cytokines, and reduced activity of ghrelin. As early asMacIntosh and co-workers 38 reported that human ageing is associated with increased cholecystokinin concentrations.
Intravenous cholecystokinin-8 infusion produces greater suppression of food intake in older adults than in younger individuals, indicating that sensitivity to the satiating effects of cholecystokinin is at least maintained with age, and might even increase. These raise the possibility of using cholecystokinin antagonists as stimulants of appetite and food intake in malnourished older people. In conclusion, ageing is accompanied by changes in ghrelin, cholecystokinin, and leptin physiology. All these changes seem to result in a ificant and clinically relevant decrease in appetite.
Future research will determine whether these changes can be corrected by pharmacological interventions. Ageing of the hypothalamic—pituitary—adrenal axis is generally associated with late-day and evening increases in cortisol concentrations, an earlier morning cortisol concentration peak, lower circadian cortisol amplitudes, and more irregular cortisol secretion patterns.
The changes in the hypothalamic—pituitary—adrenal axis that occur during ageing can have clinical implications. studies have shown that a more dynamic activity of the axis ie, a greater diurnal decline relates to better physical performance 44 and cognitive function in older adults than does a lower activity. Not only does cortisol homoeostasis change with age, but also adrenal secretion of the steroid precursor dehydroepiandrosterone DHEA and its sulphate DHEAS gradually decrease over time.
Higher concentrations of DHEA and DHEAS have been associated with psychological wellbeing and improved physical functioning, including muscle strength and bone density, and with anti-inflammatory and immunoregulatory actions. In conclusion, changes occur in cortisol secretion patterns during ageing.
The question remains whether these alterations reflect or cause ageing-associated changes in functional ability, cognition, and mood. DHEA concentrations decrease substantially during ageing, but few data point to a clinical ificance of this decrease.
Ageing of the reproductive system in women and the accompanying hormonal changes are driven by the accelerated depletion of the ovarian pool of primordial follicles, with lower oocyte quality in the remaining follicles contributing to decreased fertility from the fourth decade of life onwards. The age at which these successive events occur varies considerably, and is influenced by body composition, ethnicity, genetics, and lifestyle-related factors.
As menopausal transition progresses, cycles are more often anovulatory. Conversely, in ovulatory cycles, luteal phase duration and hormone concentrations remain stable throughout reproductive life and menopausal transition, with the exception of slowly declining mean progesterone concentrations. Changes in gonadotropin secretion throughout menopausal transition and after menopause, characterised by increased luteinising hormone LH and FSH pulse amplitude and loss of pre-ovulatory gonadotropin surges, are caused by altered feedback resulting from the intrinsically determined ovarian decline in sex steroids, inhibin A, and inhibin B production.
However, the LH-stimulated theca cells in the postmenopausal ovaries still contribute to circulating testosterone concentrations for up to 10 years. In this regard, the concentration of late postmenopausal oestrogens originating from androgen aromatisation in the peripheral tissues, although generally low compared with their concentration during the reproductive period, is still of clinical ificance, as illustrated by their association with clinical correlates such as bone fractures and breast cancer, and by the occurrence of vasomotor and articular symptoms, and the increased fracture risk during pharmacological aromatase inhibition in postmenopausal women.
Oestrogen replacement therapy can effectively inhibit the undesirable effects of menopause, such as hot flushes, accelerated bone loss, and vaginal dryness. However, the long-term risk—benefit balance remains to be determined. Since many men have a well preserved sex hormone production and fertility until old age, men do not undergo an equivalent of the menopause. Nevertheless, ageing does affect the male reproductive system. The concentration of LH increased substantially at around age 70 years.
Reproduced from Wu and colleagues, 70 by permission of Oxford University Press. However, serum concentrations of oestradiol, produced by the aromatisation of testosterone and androstenedione in peripheral tissues such as fat and striated muscles, do not decrease with ageing, although serum free oestradiol concentrations might decrease. Different mechanisms contribute to the decline in serum free and total testosterone concentrations, including a progressive, although small, increase in LH and FSH concentrations, a diminished testosterone response to exogenous LH and human chorionic gonadotropin, and a reduced of Leydig cells, all of which point towards primary testicular changes.
The inadequate increase in LH concentrations in response to the reduction in free and total testosterone in many older men reveals additional changes in gonadotropin secretion, characterised by the decreased frequency of larger amplitude LH pulses, presumably resulting from the decreased hypothalamic secretion of gonadotropin-releasing hormone, since the pituitary response to exogenous gonadotropin-releasing hormone is preserved.
The independent increase of hepatic SHBG production is a third factor, and is possibly the consequence of declining somatotropic axis activity. The relative contribution of ageing and both clinical and subclinical comorbidities to the changes in reproductive hormones in older men remains a matter of debate.
Moreover, clinical changes may in part be the cause rather than the consequence of changed sex steroid levels; 6667 low testosterone in older people is a marker of poor health, and has been linked to an increased risk of death. However, these benefits appear to be modest, and long-term data on issues of concern such as prostate and cardiovascular safety are scarce. Therefore, testosterone administration to older men is controversial outside the context of an established organic cause of hypo-gonadism. Advancing age represents a major risk factor for low bone mass and strength and a decline in muscle mass and function, leading to an increased risk of falls and fractures.
Osteoporosis is caused by an imbalance between bone-forming osteoblasts and bone-resorbing osteoclasts, the processes of which are normally coupled and influenced by als from osteocytes, which are embedded in mineralised bone and function as sensors of mechanical loading. Increasing evidence now suggests, especially from studies in rodents, that fundamental intracellular processes in the bone, such as increased oxidative stress, cell senescence, inflammation, osteocyte apoptosis, DNA damage, formation of advanced glycation end products, and a decrease in autophagy, mitochondria biogenesis, vascularity, hydration of bone, and alterations in musculoskeletal progenitor cells also play important roles in the development of osteoporosis and fragility fractures with ageing.
These age-related intrinsic mechanisms are coupled with changes in endocrine systems during ageing, and a higher incidence of endocrine diseases with age, including type 2 diabetes. We focus here on the major endocrine changes influencing bone. Oestrogens and androgens play important roles in the growth and maintenance of tissue mass and function in bones and muscles. An increase in osteocyte apoptosis occurs following the loss of ovarian or testicular function, which is mainly due to an increase in oxidative stress.
Additionally, hypogonadism is associated with the increased formation of advanced glycation end products and inflammation, thus contributing to intrinsic causes of osteoporosis that occur with ageing.
In women, the potential roles of changes in progesterone, androgen, inhibins, and FSH concentrations in enhancing the effects of oestrogen deficiency on bone loss during the perimenopausal period remain to be further defined. Sex steroids are also considered to be important in the changes in calcium and phosphate homoeostasis that occur with ageing. Postmenopausal women have higher serum phosphate concentrations than men of similar ages, and some studies have found higher serum calcium concentrations in older women than in older men, suggesting a sexual dimorphism in calcium and phosphate homoeostasis after menopause, and a potential association with sex hormone concentrations.
Oestrogen has been shown to induce renal phosphate wasting and hypophosphataemia, 84 to reduce renal calcium excretion, and to increase intestinal calcium absorption. Osteoporosis and fractures are important side-effects of the use or an excess of glucocorticoids, and are caused by effects of glucocorticoids on bone and muscle strength. They also increase bone resorption by promoting osteoclast survival. These combined effects can contribute to the age-related decline in bone mineral density, cortical porosity, and bone strength, and the increase in fractures.
Vitamin D and its metabolites and parathyroid hormone are crucial parts of the endocrine system that control whole body calcium and phosphate homoeostasis. Secondary hyperparathyroidism can also increase fracture risk, 90 as does the decline in kidney function that occurs with ageing. A study showed that older men and women, even without overt kidney disease, have an increased fracture risk with increasing serum phosphate concentrations, even when these are within the normal range, and independently of bone mineral density.
FGF23 already begins to increase during the early stages of chronic kidney disease in response to decreased phosphate excretion, but other age-related changes in this bone—kidney endocrine system have not been well studied in human beings. Growth hormone and its downstream mediator, IGF-1, are major determinants of peak bone mass. Declining concentrations of growth hormone and IGF-1 during ageing are associated with bone loss. The risks of side-effects appear to depend on many factors, such as type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used, which has led to recommendations on individualised therapy.
Glucose homoeostasis is maintained by a balance between glucose ingestion, utilisation, and production, and is under tight hormonal control by insulin. Glucose homoeostasis tends towards disequilibrium with increasing chronological age. No data have been shown to support alterations in glucose ingestion with age. The concentrations of fasting plasma glucose A and plasma glucose B after the administration of 75 g oral glucose oral glucose tolerance test were measured over time in non-diabetic individuals.
Data are means from the Baltimore Longitudinal Study of Aging BLSAfrom participants aged 20—89 years who were receiving no anti-hyperglycaemic medications. Oral glucose tolerance tests were done in all individuals at their first visit to the BLSA. The individuals presenting for their first visit were healthy with no known active disease, and were therefore not representative of the general population. Josephine M Egan, unpublished data. Insulin is secreted in a pulsatile manner comprising two stereotypical pulses: high frequency pulses with a pulse interval of about 6 min, and ultradian pulses with a pulse interval of approximately 90 min.
The liver is exposed to insulin pulses from the islets directly through the portal vein. Insulin is subject to degradation during first pass, thereby dampening the amplitude of the pulses arriving at peripheral tissues. Insulin receptor trafficking upon activation is dynamic, and dephosphorylated insulin receptor is recycled to the cell surface, a process that is synchronous with the pulsatility of insulin secretion. Additionally, insulin clearance in the liver is said to be increased in older people.
Whether ageing is responsible for the gradual deterioration in glucose disposal across the human lifespan figure 4B is a matter of ongoing debate because of confounding physical changes that occur in the body over time. In humans beings, the majority of the glucose in an oral glucose load is disposed into muscle, glucose concentrations after glucose ingestion gradually rise with age figure 4and glucose disposal becomes slower over the course of a lifetime. Studies using hyperglycaemic clamps show that this slowing in glucose disposal is probably not due to diminished total insulin secretion in response to the rising glucose.
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